Urinary tract infection (UTI) is the most common hospital-acquired infection, accounting for up to 40% of all nosocomial infections. The majority of cases of UTI are associated with the use of urinary catheters, including trans-urethral foley, suprapubic, and nephrostomy catheters. These urinary catheters are inserted in a variety of populations, including the elderly, stroke victims, spinal cord-injured patients, post-operative patients and those with obstructive uropathy. Despite adherence to sterile guidelines for the insertion and maintenance of urinary catheters, catheter-associated UTI continues to pose a major problem. For instance, it is estimated that almost one-quarter of hospitalized spinal cord-injured patients develop symptomatic UTI during their hospital course. Gram-negative bacilli account for almost 60-70%, Enterococci for about 25%, and Candida species for about 10% cases of catheter-associated UTI. Furthermore, indwelling medical devices including vascular catheters are becoming essential in the management of hospitalized patients by providing venous access. The benefit derived from these catheters as well as other types of medical devices such as peritoneal catheters, cardiovascular devices, orthopedic implants, and other prosthetic devices is often offset by infectious complications. The most common organisms causing these infectious complications are Staphylococcus epidermidis and Staphylococcus aureus. In the case of vascular catheters, these two organisms account for almost 70-80% of all infectious organisms, with Staphylococcus epidermidis being the most common organism. Candida albicans, a fungal agent, accounts for 10-15% of catheter infections.
In recent years, there have been numerous efforts to sequester antimicrobials and antibiotics on the surface of or within devices that are then placed in the vasculature or urinary tract as a means of reducing the incidence of device-related infections. These antimicrobial agents are of varying chemical composition and can include cationic polypeptides (protamine, polylysine, lysozyme, etc.), antiseptics (chlorhexidine, triclosan, etc.), surfactants (sodium dodecyl sulfate, Tween®-80, surfactin, etc.), quaternary ammonium compounds (benzalkonium chloride, tridodecyl methyl ammonium chloride, didecyl dimethyl ammonium chloride, etc.), silver ions/compounds, and nitrofurazone.
The main methods of antimicrobial catheter preparation include immersion or flushing, coating, drug-polymer conjugate and impregnating (Tunney et al., Rev. Med. Microbiol., 7(4): 195-205, 1996). In a clinical setting, suitable catheters can be treated by immersion immediately prior to placement, which offers flexibility and control to clinicians in certain situations. Several studies have examined the clinical efficacy of catheters coated with antimicrobial agents. Polyurethane catheters coated with minocycline and EDTA showed potential in reducing recurrent vascular catheter-related infections (Raad et al., Clin. Infect. Dis., 25:149-151, 1997). Minocycline and rifampin coatings have been shown to significantly reduce the risk of catheter-associated infections (Raad et al., Crit. Care Med., 26:219-224, 1998). Minocycline coated onto urethral catheters has been shown to provide some protection against colonization (Darouiche et al., Int. J. Antimicrob. Ag., 8:243-247, 1997). Johnson et al. described substantial in vitro antimicrobial activity of a commercially available nitrofurazone coated silicone catheter (Antimicrob. Agents Chemother., 43:2990-2995, 1999). The antibacterial activity of silver-containing compounds as antimicrobial coatings for medical devices has been widely investigated. Silver-sulfadiazine used in combination with chlorhexidine has received particular interest as a central venous catheter coating (Stickler, Curr. Opin. Infect. Dis., 13:389-393, 2000; Darouiche et al., New Eng. J. Med., 340: 1-8, 1999).
The loading of antimicrobial agents into medical devices by immersion or coating technologies has the advantage of being relatively simple. However, the limited mass of drug that can be incorporated may be insufficient for a prolonged antimicrobial effect, and the release of the drug following clinical insertion of the device is rapid and relatively uncontrolled. A means of reducing these problems is by direct incorporation of the antimicrobial agent into the polymeric matrix of the medical device at the polymer synthesis stage or at the device manufacture stage. Rifampicin has been incorporated into silicone in an attempt to prevent infection of cerebrospinal fluid shunts with some success (Schierholz et al., Biomaterials, 18:839-844, 1997). Iodine has also been incorporated into medical device biomaterials. Coronary stents have been modified to have antithrombogenic and antibacterial activity by covalent attachment of heparin to silicone with subsequent entrapment of antibiotics in cross-linked collagen bound to the heparinized surface (Fallgren et al., Zentralbl. Bakteriol., 287:19-31, 1998).
Welle et al. disclosed the method of preparing a kit for flushing a medical device (U.S. Pat. No. 6,187,768). The kit includes a solution containing an antibiotic, an anticoagulant (protamine sulfate) and an antithrombotic agent or chelating agent useful for preventing infections caused by bacterial growth in catheters.
Raad et al. disclosed that pharmaceutical compositions of a mixture of minocycline and EDTA were useful in maintaining the patency of a catheter port (U.S. Pat. No. 5,362,754). Recently, Raad and Sheretz further disclosed that effective catheter flush solutions could be prepared with non-glycopeptide antimicrobial agent, an antithrombic agent, an anticoagulant, and a chelating agent selected from the group consisting of EDTA, EGTA and DTPA (U.S. Pat. No. 5,688,516).
Welle et al. teach the use of several anticoagulants for use in medical devices, including protamine sulfate (U.S. Pat. No. 6,187,768). Combinations of protamine sulfate and certain antibiotics have been shown to have synergistic effects on catheter-associated bacteria such as Pseudomonas aeruginosa and Staphylococcus epidermidis (Soboh et al., Antimicrob. Agents. Chemother., 39: 1281-1286, 1995; Richards et al., ASAIO Trans, 36:296-299). Kim et al. (Am. J. Kidney Dis., 39: 165-173, 2002) developed an antimicrobial-impregnated peritoneal dialysis catheter by impregnating the cuff and tubing with chlorhexidine, silver-sulfadiazine and triclosan in a polymer matrix. Fox et al. disclose medical devices having the synergistic composition comprising a silver salt and chlorhexidine (U.S. Pat. No. 5,019,096). Soloman et al. disclose anti-infective medical articles containing chlorhexidine (U.S. Pat. No. 6,261,271). Modak et al., in U.S. Pat. Nos. 6,706,024 and 6,843,784, disclose chlorhexidine, triclosan, and silver compound containing medical devices.